Genome-wide measures of DNA methylation in peripheral blood and the risk of urothelial cell carcinoma: A prospective nested case-control study

Pierre Antoine Dugué, Maree T. Brinkman, Roger L Milne, Ee Ming Wong, Liesel M. Fitzgerald, Julie K Bassett, Jihoon E. Joo, Chol-Hee Jung, Enes Makalic, Daniel F. Schmidt, Daniel J. Park, Jessica Chung, Anthony D. Ta, Damien Michael Bolton, Andrew Lonie, Anthony Longano, John L. Hopper, Gianluca Severi, Richard Saffery, Dallas R. EnglishMelissa C. Southey, Graham G. Giles

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19 Citations (Scopus)

Abstract

Background: Global DNA methylation has been reported to be associated with urothelial cell carcinoma (UCC) by studies using blood samples collected at diagnosis. Using the Illumina HumanMethylation450 assay, we derived genome-wide measures of blood DNA methylation and assessed them for their prospective association with UCC risk. Methods: We used 439 case-control pairs from the Melbourne Collaborative Cohort Study matched on age, sex, country of birth, DNA sample type, and collection period. Conditional logistic regression was used to compute odds ratios (OR) of UCC risk per s.d. of each genome-wide measure of DNA methylation and 95% confidence intervals (CIs), adjusted for potential confounders. We also investigated associations by disease subtype, sex, smoking, and time since blood collection. Results: The risk of superficial UCC was decreased for individuals with higher levels of our genome-wide DNA methylation measure (OR=0.71, 95% CI: 0.54-0.94; P=0.02). This association was particularly strong for current smokers at sample collection (OR=0.47, 95% CI: 0.27-0.83). Intermediate levels of our genome-wide measure were associated with decreased risk of invasive UCC. Some variation was observed between UCC subtypes and the location and regulatory function of the CpGs included in the genome-wide measures of methylation. Conclusions: Higher levels of our genome-wide DNA methylation measure were associated with decreased risk of superficial UCC and intermediate levels were associated with reduced risk of invasive disease. These findings require replication by other prospective studies.

Original languageEnglish
Pages (from-to)664-673
Number of pages10
JournalBritish Journal of Cancer
Volume115
Issue number6
DOIs
Publication statusPublished - 6 Sep 2016
Externally publishedYes

Keywords

  • biomarker
  • bladder cancer
  • DNA methylation
  • EWAS
  • peripheral blood
  • urothelial cell carcinoma

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